We have distinguished fatigue, in response to tetanic stimulation, from post-tetanic potentiation in single muscle fibers of the frog. We have shown that fatigue, as measured by a decline in tetanic tension and the response to short electrical stimuli, is produced when glycogen and ATP concentrations are close to normal and when phosphocreatine is depleted. We conclude that fatigue in these circumstances is due to failure of excitation-contraction coupling, due possibly to accumulation of lactate and H ion and interference with calcium kinetics, as fatigued muscles can consume residual ATP and produce a contracture when they are exposed to caffeine. Functional failure prior to exhaustion of available high energy metabolites may represent a protective mechanism that prevents death of muscle as well as neuronal cells. BIBLIOGRAPHIC REFERENCE: Vergara, J.L., Rapoport, S.I., and Nassar-Gentina, V.: Fatigue and post-tetanic potentiation in single muscle fibers of the frog. American J. Physiology 232: C185-C190, 1977.